BackgroundPatients with broad HLA sensitization have poor access to donor organs, high mortality while waiting for kidney transplant, and inferior graft survival. Although desensitization strategies permit transplantation via lowering of donor-specific antibodies, the B cell–response axis from germinal center activation to plasma cell differentiation remains intact.MethodsTo investigate targeting the germinal center response and plasma cells as a desensitization strategy, we sensitized maximally MHC-mismatched rhesus pairs with two sequential skin transplants. We administered a proteasome inhibitor (carfilzomib) and costimulation blockade agent (belatacept) to six animals weekly for 1 month; four controls received no treatment. We analyzed blood, lymph node, bone marrow cells, and serum before desensitization, after desensitization, and after kidney transplantation.ResultsThe group receiving carfilzomib and belatacept exhibited significantly reduced levels of donor-specific antibodies (P=0.05) and bone marrow plasma cells (P=0.02) compared with controls, with a trend toward reduced lymph node T follicular helper cells (P=0.06). Compared with controls, carfilzomib- and belatacept-treated animals had significantly prolonged graft survival (P=0.02), and renal biopsy at 1 month showed significantly reduced antibody-mediated rejection scores (P=0.02). However, four of five animals with long-term graft survival showed gradual rebound of donor-specific antibodies and antibody-mediated rejection.ConclusionsDesensitization using proteasome inhibition and costimulation blockade reduces bone marrow plasma cells, disorganizes germinal center responses, reduces donor-specific antibody levels, and prolongs allograft survival in highly sensitized nonhuman primates. Most animals experienced antibody-mediated rejection with humoral-response rebound, suggesting desensitization must be maintained after transplantation using ongoing suppression of the B cell response.

Neurosurgery in Uganda was virtually non-existent up until late 1960s. This changed when Dr. Jovan Kiryabwire spearheaded development of a neurosurgical unit at Mulago Hospital in Kampala. His work ethic and vision set the stage for rapid expansion of neurosurgical care in Uganda.At the beginning of the 2000s, Uganda was a country of nearly 30 million people, but had only 4 neurosurgeons. Neurosurgery's progress was plagued by challenges faced by many developing countries, such as difficulty retaining specialists, lack of modern hospital resources, and scarce training facilities. To combat these challenges 2 distinct programs were launched: 1 by Dr. Benjamin Warf in collaboration with CURE International, and the other by Dr. Michael Haglund from Duke University. Dr. Warf's program focused on establishing a facility for pediatric neurosurgery. Dr. Haglund's program to increase neurosurgical capacity was founded on a "4 T's Paradigm": Technology, Twinning, Training, and Top-Down. Embedded within this paradigm was the notion that Uganda needed to train its own people to become neurosurgeons, and thus Duke helped establish the country's first neurosurgery residency training program.Efforts from overseas, including the tireless work of Dr. Benjamin Warf, have saved thousands of children's lives. The influx of the Duke Program caused a dynamic shift at Mulago Hospital with dramatic effects, as evidenced by the substantial increase in neurosurgical capacity. The future looks bright for neurosurgery in Uganda and it all traces back to a rural village where 1 man had a vision to help the people of his country.

The purpose of this review is to discuss immunologic tolerance as it applies to solid organ transplantation and to identify barriers that hinder the achievement of this long-term goal. First, the definition of tolerance and an introduction of mechanisms by which tolerance exists or can be achieved will be discussed. Next, a review of contemporary attempts at achieving transplant tolerance will be described. Finally, a discussion of the humoral barriers to transplantation tolerance and potential ways to overcome these barriers will be presented.

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Achieving a target radiation dose of 45.0 to 50.4 Gy is associated with a survival benefit in patients with locally advanced rectal cancer. Aligning all aspects of multimodal oncology care may increase the probability of completing neoadjuvant therapy.

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Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anti-coagulation is difficult due to bleeding. A novel ‘cytotopic’ agent, ‘Thrombalexin’, (TLN) combines a cell-membrane bound (mirystoyl tail) anti-thrombin (HLL peptide) which can be perfused directly to the donor organ or cells. Thromboelastography (TEG) was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN vs. HLL (without cytotopic tail) vs. negative-control. Both TLN and HLL treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells (EC) and neonatal porcine islets (NPI) prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and FACS. In vivo, perfusion of a NHP kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to four days after transplantation. There was no platelet deposition and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis) were less in the TLN treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated.

Background: Pancreatic acinar cell carcinoma (pACC) is a rare malignancy and surgical utilization has been historically low in these patients. Contemporary outcomes for this patient population remain unknown. Methods: The 1998-2012 National Cancer Data Base was queried for baseline characteristics in patients with pACC. Patients with potentially operable disease (stage I/II) were grouped by surgical resection. Multivariable logistic regression was used to predict factors associated with resection. Survival was estimated using Kaplan-Meier analysis. A proportional hazards model identified factors associated with overall survival.Results: 980 patients were identified. Mean age at diagnosis was 64 years. Tumors were more common in men (68%), white patients (88%), and within the pancreatic head (57%). Thirty-four percent of patients with localized disease failed to undergo resection. Five-year survival was higher among patients who underwent resection (42% vs. 9%, p < 0.001). In patients with resectable disease, male sex, older age, black race, tumors within the pancreatic head, lower grade tumors and treatment at non-academic centers are associated with failure to undergo surgery. Conclusion:Patients with localized pACC have increased survival after resection. However, in this contemporary analysis, resection continues to be underutilized and new efforts to increase resection rates should be undertaken.